Veterans have a higher incidence of cardiovascular disease than the general population. Cardiovascular disease risk is caused by environmental and heritable factors. The broad goal of our research is to understand how these factors interact to determine overall disease risk. In current funding period of this award we studied how heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3) associate with heritable coronary artery disease risk. We showed that disease risk associated loci within the final intron of the gene decrease expression of the gene in blood and vascular cells and that PLPP3 deficiency in mice results in accelerated atherosclerosis. Our findings support the concept that PLPP3 functions as an ?atherosclerosis suppressor? gene and that heritable variants that decrease expression of the gene promote heart disease risk. LPP3 is an integral membrane cell surface enzyme that can dephosphorylate and inactivate bioactive lipid mediators. One of these LPP3 substrates, lysophosphatidic acid (LPA) acts on multiple blood and vascular cells to promote inflammation and cardiovascular disease progression. In mice, genetic or pharmacological targeting of LPA modulates atherosclerosis. In our mouse studies, LPP3 deficiency was associated with increased levels of LPA in the blood and vascular tissues. These results support our overarching hypothesis that dephosphorylation and inactivation of LPA underlies the normally protective effect of LPP3 on cardiovascular disease focusing attention on the sources of bioactive LPA in the blood and vasculature. In preliminary studies we found that circulating levels of LPA are very sensitive to diet in mice and humans. This diet sensitive pool of LPA is largely associated with atherogenic lipoproteins that are formed in the intestine from dietary fats and lipids (chylomocrons and their remnants) or are made in the liver (low density lipoproteins). LPA in blood plasma can be made from lysoglycerophospholipids by autotaxin (ATX) which is a secreted lysophospholipase D enzyme supporting the hypothesis that exogenous and endogenous sources of circulating LPA come from lysophospholipids that are formed in the intestine or the liver. LPA is also an intermediate in the synthesis of triglycerides by the intestine and liver so, since this process is coupled to the generation of these atherogenic lipoproteins it is also possible that plasma LPA is generated de novo.
The first aim of this proposal will test these competing hypotheses directly by using stable isotope tracers and mass spectrometry studies in mice and humans to directly identify precursors of circulating LPA. The mouse studies will allow us to use genetic and pharmacological approaches to selectively manipulate ATX, LPP3 and the formation and clearance of intestinal and hepatic derived lipoproteins. Atherogenic lipoproteins elicit signaling responses in blood and vascular cell types that underlie the initiation and progression of cardiovascular disease by promoting permeability of vascular endothelium, phenotypic modulation and proliferation/migration of vascular smooth muscle cells and the classical macrophage foam cell response.
The second aim of the proposal will test the hypothesis that the LPA content of these lipoproteins is a determinant of these responses. LPA is present in atherosclerotic blood vessels and release of LPA may contribute to platelet activation and thrombosis during plaque rupture.
The final aim of this proposal will use state of the art mass spectrometry based imaging to test the hypothesis that atheroma associated LPA accumulates progressively as a result of lipoprotein extravasation during the development of atherosclerosis. Together, these studies will build on the research accomplished during the present funding period by providing important new information about the impact of diet on a bioactive lipid signaling pathway that is now strongly implicated in heritable cardiovascular disease risk. This research could inform strategies to mitigate cardiovascular disease risk through dietary interventions that decrease atherogenic lipoprotein associated LPA and will further underscore the value of pharmacological targeting of LPA metabolism and signaling to mitigate cardiovascular disease risk.

Public Health Relevance

Veterans have a higher incidence of heart disease than the general population. Heart disease risk is caused by inherited (ie family history) and environmental factors. The most powerful environmental determinant of cardiovascular disease risk is the diet. Unhealthy diets promote obesity and dramatically increase cardiovascular disease risk in men and women because obese individuals and particularly those with diabetes have persistently high levels of ?bad? lipids in their blood called low density lipoproteins. These are formed directly from fats and lipids that are ingested in the diet and can also be produced by the liver. Accumulation of these bad lipids in the walls of blood vessels in the heart causes angina and heart attacks. We have identified a particular component of these bad lipids that can increase these heart disease processes and may be a link between heritable and diet dependent heart disease risk. We will study where this particular bad lipid comes from in the body. Our studies might lead to new ways to prevent, diagnose or treat heart disease in Veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX001550-06
Application #
9415985
Study Section
Cardiovascular Studies B (CARB)
Project Start
2013-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA Medical Center - Lexington, KY
Department
Type
DUNS #
018766373
City
Lexington
State
KY
Country
United States
Zip Code
40502
Gomez-Cambronero, J; Morris, A J; Henkels, K M (2017) PLD Protein-Protein Interactions With Signaling Molecules and Modulation by PA. Methods Enzymol 583:327-357
Keune, Willem-Jan; Potjewyd, Frances; Heidebrecht, Tatjana et al. (2017) Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators. J Med Chem 60:2006-2017
Dobierzewska, Aneta; Soman, Sony; Illanes, Sebastian E et al. (2017) Plasma cross-gestational sphingolipidomic analyses reveal potential first trimester biomarkers of preeclampsia. PLoS One 12:e0175118